Although many agents can induce apoptosis, they commonly are associated with unappealing side effects that can compromise the health of the organism. The recently identified protein TRAIL (TNF-related apoptosis-inducing ligand) is generating tremendous excitement because it induces apoptosis in a wide range of tumor cells but not in normal, benign cells and tissues. Preclinical studies have shown systemic doses of TRAIL are safe and can suppress tumor growth in vivo. However, large amounts of TRAIL were needed to inhibit tumor formation, because of the short in vivo half-life of the TRAIL protein, and the antitumor activity of systemically administered soluble TRAIL was highest when given shortly after tumor implantation. Due of these issues, an alternative means of delivery may increase the relative activity of TRAIL such that larger, more established tumors can be eradicated as efficiently as smaller tumors. This year in the United States approximately 30,000 new cases of renal cell carcinoma (RCC) will be diagnosed and nearly 12,000 deaths are expected from RCC, which comprised 3% of all deaths attributable to adult cancers. Metastatic RCC carries a median survival of 8 months and almost 30% of RCC patients are diagnosed with advanced metastatic disease. Furthermore, RCC is highly resistant to chemotherapy, a possible consequence of its association with the multidrug-resistance P-glycoprotein. Consequently, immunotherapy has been intensely studied as a possible treatment for this disease. Unfortunately, the response rates following have been poor and significant toxicity reported, resulting in the limited use of immunotherapy in the treatment of RCC. Gene transfer therapy offers new alternatives in the treatment of RCC. Employment of various gene delivery systems, such as non-replicative viral vectors, is making it possible to administer genes directly into tumors sites in situ. Previous work from our laboratory has described the cytotoxic activity of TRAIL against human RCC cell lines, and the development and testing of a recombinant, replication-deficient adenoviral vector encoding the human TRAIL gene (Ad5-TRAIL). Transfer of the TRAIL gene into human tumor cells in vitro and in vivo, using immunodeficient mice, led to the rapid production and expression of TRAIL protein, resulting in the apoptotic death of the tumor cells. However, it remains unknown whether Ad5-TRAIL will inhibit tumor growth in immunocompetent animals, and if the Ad5-TRAIL-induced tumor cell death will activate systemic antitumor immunity. With this in mind, the proposed project will employ a novel adenoviral vector encoding the mouse TRAIL gene (Ad5-mTRAIL) combined with agents to boost systemic immune responses to develop unique approaches for the treatment of RCC. Specific Aims: (1) Characterize a mouse model of renal cancer to examine the influence of Ad5-mTRAIL-induced apoptotic tumor cell death on the activation of systemic antitumor immunity, and (2) Examine the ability of immunostimulatory cytokines and DC mobilizing/activating agents to augment the Ad5-mTRAIL-induced immune response.